Peripheral neuropathy is one of the major complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function in the damaged peripheral nervous system after diabetes. Cyclic guanosine-monophosphate (GMP) is involved in the regulation of many neural functions. The phosphodiesterase-5 (PDE5) enzyme is highly specific for hydrolysis of cGMP. The role of PDE5 in diabetic peripheral neuropathy has not been fully investigated. In a novel set of experiments, our data show that hyperglycemia upregulates PDE5 expression and suppression of PDE5 by sildenafil, a specific inhibitor of PDE5, increases cGMP levels and significantly improves neurological outcome in diabetic mice, indicating that sildenafil may have a beneficial effect on the clinical treatment of diabetic peripheral neuropathy In this application, we therefore seek to investigate the mechanisms underlying the therapeutic effects of inhibition of PDE5 by sildenafil on the treatment of diabetic peripheral neuropathy. We propose that sildenafil and tadalafil by suppressing PDE5 activity ameliorates diabetic peripheral neuropathy. Our hypotheses are: 1. Treatment with PDE5 inhibitors, sildenafil and tadalafil, improves neurological function of peripheral neuropathy in diabetic mice. 2. Sildenafil by suppressing PDE5 increases cGMP levels in diabetic Schwann cells and dorsal root ganglia (DRG) neurons, leading to activation of the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway that mediates sildenafil-enhanced axonal outgrowth and myelination. 3. NGF and BDNF upregulated by sildenafil-activated cGMP/PKG signaling pathway mediate axonal outgrowth and myelination. The proposed experiments have been designed to test these hypotheses. To investigate the effect of PDE5 inhibitors on neurological outcome, type II diabetic mice which develop severe peripheral neuropathy will be treated with sildenafil and tadalafil. To investigate the molecular mechanisms that mediate sildenafil-enhanced axonal outgrowth and myelination in diabetic mice, the effect of sildenafil on expression of PDE5, cGMP, and activation of cGMP/PKG signaling pathways will be examined. Using pharmacological analogs, inhibitors and transgenic mice, we will investigate the cause-effect of the cGMP/PKG signaling pathway and NGF and BDNF on regulating sildenafil-enhanced axonal outgrowth and myelination. These studies are innovative and will provide new insight into mechanisms underlying the neurological dysfunction of diabetic peripheral neuropathy and lead to the development of a new treatment using PDE5 inhibitors. Relevance Statement: Peripheral neuropathy often stemming from diabetes is a major disability affecting millions of Americans. In this proposal, I seek to develop a novel treatment for peripheral neuropathy using PDE5 inhibitors, sildenafil and tadalafil. These drugs, clinically employed for the treatment of erectil dysfunction, are shown to be highly effective in substantially reducing neurological dysfunction caused by diabetes. The molecular mechanism by which sildenafil is therapeutically effective is elucidated.